The E2F/Rb pathway is central to the regulation of the mammalian cell cycle, and thus, it appears a reasonable target for the development of chemotherapeutic agents (see Sage J. Hope in sight for retinoblastoma. Nat Med 2007; 13:30-1; La Thangue N B. The yin and yang of E2F-1: balancing life and death. Nat Cell Biol 2003; 5:587-9; and Johnson D G, Degregori J. Putting the Oncogenic and Tumor Suppressive Activities of E2F into Context. Current molecular medicine 2006; 6:731-8). The E2F family is composed of nine members with various biological roles (see Kong L J, Chang J T, Bild A H, Nevins J R. Compensation and specificity of function within the E2F family. Oncogene 2007; Trimarchi J M, Lees J A. Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol 2002; 3:11-20; and Crosby M E, Almasan A. Opposing roles of E2Fs in cell proliferation and death. Cancer Biol Ther 2004; 3:1208-11). E2F1 is the best studied member of the family and has been shown to have numerous and even opposing roles in cell growth control depending on the context of experimentation. In the context of drug-induced apoptosis of highly transformed cells, E2F1 is downstream target of the ATM/ATR signaling pathway and contributes significantly to the apoptotic activity of DNA damaging drugs and cyclin dependent kinase inhibitors (Lin W C, Lin F T, Nevins J R. Selective induction of E2F1 in response to DNA damage, mediated by ATM-dependent phosphorylation. Genes Dev 2001; 15:1833-44). In contrast, E2F4 (the most abundant member of the E2F family) contributes to survival in the context of treatment with chemotherapeutic drugs or cdk inhibitors (see Ma Y, Freeman S N, Cress W D. E2F4 Deficiency Promotes Drug-Induced Apoptosis. Cancer Biol Ther 2004; 3:1262-9; Ma Y, Cress W D, Haura E B. Flavopiridol-induced apoptosis is mediated through up-regulation of E2F1 and repression of Mcl-1. Mol Cancer Ther 2003; 2:73-81; DuPree E L, Mazumder S, Almasan A. Genotoxic stress induces expression of E2F4, leading to its association with p130 in prostate carcinoma cells. Cancer Res 2004; 64:4390-3; and Crosby M E, Jacobberger J, Gupta D, Macklis R M, Almasan A. E2F4 regulates a stable G(2) arrest response to genotoxic stress in prostate carcinoma. Oncogene 2006; 26:1897-909).
While individual members of the E2F family have specialized roles, a variety of complementary approaches have shown that down regulation of total intracellular E2F activity can lead to apoptosis, growth arrest or both (see Montigiani S, Muller R, Kontermann R E. Inhibition of cell proliferation and induction of apoptosis by novel tetravalent peptides inhibiting DNA binding of E2F. Oncogene 2003; 22:4943-52; Wu C L, Classon M, Dyson N, Harlow E. Expression of dominant-negative mutant DP-1 blocks cell cycle progression in G1. Mol Cell Biol 1996; 16:3698-706; Fabbrizio E, Le Cam L, Polanowska J, et al. Inhibition of mammalian cell proliferation by genetically selected peptide aptamers that functionally antagonize E2F activity. Oncogene 1999; 18:4357-63; and Bandara L R, Girling R, La Thangue N B. Apoptosis induced in mammalian cells by small peptides that functionally antagonize the Rb-regulated E2F transcription factor. Nat Biotechnol 1997; 15:896-901).